The role of the posterior cingulate cortex (PCC) in memory is debated within human
cognitive neuroscience. Recent proposals posit that the PCC is a component of a large-scale
cortico-hippocampal network that supports episodic sequencing and recollection, named
the posterior medial (PM) network (Ranganath and Ritchey, 2012; Inhoff and Ranganath,
2017). Attempts to deconstruct the PM network are in their infancy (Ritchey and Cooper,
2020), but it has been shown that event-specific reactivation in the PCC correlates
with recall of episodic details (Bird et al., 2015). This work suggests that the PCC
has an active role in the consolidation of episodic memories. However, numerous fMRI
studies have also observed that successful encoding is associated with greater PCC
deactivation (for review, see Huijbers et al., 2012). This pattern—part of the “encoding/retrieval
flip” phenomenon (Daselaar et al., 2009)—instead implies that attenuation of PCC activity
during encoding might facilitate memory.
In a novel study combining deep brain stimulation (DBS) and stereotactic encephalography
in humans, Natu et al. (2019) explored whether PCC stimulation (~100 Hz)—assumed to
be inhibitory—would improve memory and modulate hippocampal activity, if applied during
the encoding-phase of a verbal free-recall task. While stimulation did modulate hippocampal
gamma and theta oscillations, it also led to a mild behavioral impairment, primarily
driven by poorer recall for early items in a series (i.e., reduced primacy effect).
Subsequent analyses indicated that the hippocampal modulations, particularly in the
low gamma band, correlated with memory disruption. The authors concluded that their
findings imply a causal role for the PCC in episodic encoding.
Although this work makes an important and valuable contribution to our understanding
of the role of the PCC, there is scope for further investigation. In this commentary,
we examine the extent to which the conclusions are supported, with the aim of raising
broader questions for the field. We draw on various methodological and theoretical
considerations, highlighting potential avenues for future research.
Experimental Controls
DBS confers a unique opportunity to selectively stimulate brain regions and observe
the behavioral results, affording a level of causal inference unmatched by other methods
used in human neuroscience (Poldrack and Farah, 2015). In this regard, the use of
DBS is a strength of Natu et al. (2019) study. However, as the authors did not examine
the effect of stimulation on a control task, or in a control region, it remains possible
that the observed effects were neither specific to the PCC nor episodic encoding.
From a process-based view, it is plausible that stimulation disrupted attentional
processes rather than memory processes. It is understood that the allocation of attention
contributes to the primacy effect (e.g., Brown et al., 2000), and the PCC has been
proposed to play an important role in controlling attentional focus (Leech and Sharp,
2014). To reject such explanations and demonstrate a specific causal role for the
PCC in episodic encoding, the inclusion of control tasks with little episodic-mnemonic
demand, such as the spatial-cueing task, would be beneficial.
Mechanism(s) of DBS
Despite its widespread clinical use, the mechanism(s) of DBS remain elusive (Chiken
and Nambu, 2016). Contemporary research suggests that DBS acts through multiple mechanisms
rather than simple local excitatory and/or inhibitory mechanisms (Ashkan et al., 2017).
Accordingly, predicting whether stimulation will have a net excitatory or inhibitory
effect, and the subsequent impact on behavior, is challenging. Moreover, research
using closed-loop stimulation—a system in which stimulation is determined by recorded
brain signals rather than fixed parameters—has shown that the effect of stimulation
on episodic memory is state-dependent; it depends on the timing of stimulation relative
to the brain's encoding state (Ezzyat et al., 2017, 2018). Therefore, without knowing
the effect of stimulation, interpretation is challenging.
Stimulation Parameters
Studies using DBS to examine memory processes often differ in sample size, amplitude
and frequency of stimulation, and memory task (Suthana et al., 2018). Although all
these factors could influence the results, differences in stimulation parameters (e.g.,
amplitude and frequency) are perhaps the most consequential. This is problematic for
the authors' claim that the PCC's role in encoding is separate from that of the hippocampus,
as it is primarily based on comparisons with a study that applied a different frequency
of stimulation (~50 Hz) to the hippocampus/entorhinal cortex (Goyal et al., 2018).
They describe that both studies observed a stimulation-related effect on primacy but
that PCC stimulation increased temporal-clustering (i.e., the tendency to cluster
recalled items based on their proximity in the encoding-phase) whereas hippocampus/entorhinal
cortex stimulation decreased temporal-clustering. However, due to the different stimulation
frequencies applied, it is difficult to draw such conclusions. Research that systematically
examines the effect(s) of stimulation parameters on memory is necessary to facilitate
concrete claims of causality in DBS memory research.
Electrode Localization
When describing the electrode locations, Natu et al. (2019, p. 7,175) state that,
“all electrodes were targeted to the retrosplenial region of the PCC, using the splenium
of the corpus callosum as a landmark.” Given that this region comprised Brodmann areas
26, 29, 30, and the ventral portion of area 23, the stimulated region actually included
two areas of cortex: PCC and retrosplenial cortex (Vogt, 2009). This complicates interpretation,
as the PCC and retrosplenial cortex are both components of the PM network and may
support different representations and/or processes (Ritchey and Cooper, 2020). While
we appreciate the challenge of selectively stimulating these regions in vivo, it is
important to note that the findings may result from combined PCC/retrosplenial cortex
stimulation.
Conclusion
Numerous fMRI studies implicate the PCC in memory, although its exact role remains
undetermined. Here, we critically reviewed the findings of (Natu et al., 2019) study,
which used DBS to attenuate PCC activity during encoding. Their observation that stimulation
impaired recall prima facie suggests that the PCC actively supports encoding, a finding
that appears to stand in contrast to predictions based on the “encoding/retrieval
flip.” However, there are methodological and theoretical considerations that hinder
this conclusion, and call for further investigation. Through this commentary, we hope
to call attention to this fascinating topic and highlight important considerations
for future memory research using DBS.
Author Contributions
All authors listed have made a substantial, direct and intellectual contribution to
the work, and approved it for publication.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.